MS01.01 Biological Mechanisms of Resistance

Abstract

Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have transformed the management of non-small cell lung cancer (NSCLC). Despite the dramatic and sometimes durable activity of these agents, a majority of patients will progress on therapy.1 Patients who experience a de novo lack of response to initial therapy are deemed as having primary (intrinsic) resistance. By contrast, acquired resistance refers to patients who initially achieve an objective response to therapy but eventually progress over time. The mechanistic basis for primary versus acquired resistance to immune checkpoint inhibitors is still poorly defined. To date, studies into the biological mechanisms of resistance to immunotherapies have centered around preclinical studies and analyses of repeat biopsies obtained from patients at the time of disease progression.2 These efforts have been complemented by similar studies in other immuno-oncology settings (e.g., melanoma),3,4 since there is potential for shared biology underlying immunotherapy resistance across malignancies. Both tumor cell-intrinsic and tumor cell-extrinsic factors have been implicated in mediating resistance to immunotherapies.2 In the setting of primary resistance, disease progression is commonly driven by a lack of neoantigens sufficient to illicit an initial immune response, commonly due to a low tumor mutation burden.5 Alternatively, tumors may actually harbor antigens capable of generating an immune response, but defects in antigen processing may ultimately limit the presentation of these antigens on the cell surface via MHC. Defective antigen presentation may be due to loss of beta-2 microglobulin (B2M), elimination of transporters associated with antigen processing (TAP) proteins, or downregulation of HLA.2,3 In addition, intrinsic resistance to immune checkpoint inhibitors may be due to altered oncogenic cell signaling (e.g., WNT/B-catenin pathway) and/or tumor de-differentiation with impaired antigen expression. Molecular mechanisms of acquired resistance to checkpoint blockade likely include many of the same processes as those implicated in intrinsice resistance. Indeed, homozygous loss of B2M, which is required for stabilization of HLA on the cell surface, has been described in NSCLC at the time of acquired resistance to PD-1 pathway blockade.6 Additionally, neoantigen loss through elimination of specific tumor subclones (i.e., immunoediting), genetic alterations in interferon gamma (IFN) signaling, and upregulation of alternative checkpoints (e.g., TIM3) have also been purported to confer acquired resistance to checkpoint inhibitors.4,7,8 At present, the relative frequencies of these processes and the interplay among them within NSCLC and other malignancies remains to be defined. Moving forward, it will be critical to pursue more in-depth preclinical and clinical studies of resistance to PD-1 pathway blockade in NSCLC. Just as insights into the molecular mechanisms of resistance to targeted therapy have transformed the therapeutic landscape for oncogene-driven tumors, it will be imperative for immuno-oncology to develop a framework for understanding resistance to checkpoint inhibitors and apply this framework to clinical development of next-generation immuno-onclogy agents. This is especially critical due to the sheer number of immuno-oncology combinations currently in clinical testing. Ultimately, knowledge of the mechanisms of resistance to immune checkpoint inhibitors may help better inform the rationale design of trials evaluating PD-1 inhibitor combinations. 1. Garon EB, et al. J Clin Oncol 2019 Jun 2 [Epub ahead of print]. 2. Sharma P, et al. Cell 2017;168(4):707-23. 3. Sade-Feldman M, et al. Nat Commun 2017;8(1):1136. 4. Zaretsky JM, et al. NEJM 2016;375:819-29. 5. Rizvi NA, et al. Science 2015;348(6230):124-128. 6. Gettinger S, et al. Cancer Discov 2017:7:1420-35. 7. Anagnostou V, et al. Cancer Discov 2017;7(3):264-76. 8. Koyama S, et al. Nat Commun 2016;7:10501. Immunotherapy, resistance, PD-1 blockade